Methamphetamine Self-Administration Causes Persistent Striatal Dopaminergic Alterations and Mitigates the Deficits Caused by a Subsequent Methamphetamine Exposure

Abstract

Preclinical studies have demonstrated that repeated methamphetamine (METH) injections (referred to herein as a "binge" treatment) cause persistent dopaminergic deficits. A few studies have also examined the persistent neurochemical impact of METH self-administration in rats, but with variable results. These latter studies are important because: 1) they have relevance to the study of METH abuse; and 2) the effects of noncontingent METH treatment do not necessarily predict effects of contingent exposure. Accordingly, the present study investigated the impact of METH self-administration on dopaminergic neuronal function. Results revealed that self-administration of METH, given according to a regimen that produces brain METH levels comparable with those reported postmortem in human METH abusers (0.06 mg/infusion; 8-h sessions for 7 days), decreased striatal dopamine transporter (DAT) uptake and/or immunoreactivity as assessed 8 or 30 days after the last self-administration session. Increasing the METH dose per infusion did not exacerbate these deficits. These deficits were similar in magnitude to decreases in DAT densities reported in imaging studies of abstinent METH abusers. It is noteworthy that METH self-administration mitigated the persistent deficits in dopaminergic neuronal function, as well as the increases in glial fibrillary acidic protein immunoreactivity, caused by a subsequent binge METH exposure. This protection was independent of alterations in METH pharmacokinetics, but may have been attributable (at least in part) to a pretreatment-induced attenuation of bingeinduced hyperthermia. Taken together, these results may provide insight into the neurochemical deficits reported in human METH abusers.

Dopamine D3 receptors contribute to methamphetamine-induced alterations in dopaminergic neuronal function: Role of hyperthermia

“…To examine whether the ability of PG01037 to attenuate the effects of multiple methamphetamine injections on DAT uptake was related to attenuation of methamphetamine-induced hyperthermia, in the second experiment, rats were treated in a warm ambient environment (a common practice used to promote methamphetamine-induced hyperthermia; see, for example Bowyer et al, 1993; Hadlock et al, 2010; McFadden et al, 2011; Myles et al, 2008). Results indicate that PG01037 failed to attenuate the methamphetamine-induced decreases in DAT (Fig.…”

Methamphetamine self-administration attenuates hippocampal serotonergic deficits: role of brain-derived neurotrophic factor

“…Food training and self-administration occurred in an operant chamber (Coulbourn Instruments, Whitehall, PA USA) as described in McFadden et al, 2012AB. Rats underwent 7 d of self-administration (8 h/session; FR1; 0.12 mg/infusion racemic-METH expressed as free-base or saline; generously supplied by the National Institute on Drug Abuse, National Institute of Health, Bethesda, MD) during the light cycle as previously described (McFadden et al, 2012AB).…”

“…Of note these dosing paradigms often lead to attenuated persistent deficits compared to those animals only given METH in a “binge-like” pattern (e.g., 3–6 injections, 7.5–50 mg/kg/injection, 2–8-h intervals; Johnson-Davis et al, 2003; Belcher et al, 2008; Cadet et al, 2009; McFadden et al, 2012AB). Specifically, the protection afforded by the escalating doses of METH results in attenuated persistent deficits in 5HT content and SERT binding in the hippocampus (Johnson-Davis et al, 2003; Belcher et al, 2008).…”

“…Specifically, the protection afforded by the escalating doses of METH results in attenuated persistent deficits in 5HT content and SERT binding in the hippocampus (Johnson-Davis et al, 2003; Belcher et al, 2008). Prior self-administration of METH that leads to escalating METH intake also attenuates the persistent deficits induced by a binge METH exposure in the hippocampus and striatum (McFadden et al, 2012AB). Despite these findings, the mechanism underlying this protection is not clearly understood.…”

Chronic Nicotine Exposure Attenuates Methamphetamine-Induced Dopaminergic Deficits

“…Repeated METH administrations to humans (Sekine et al, 2001;Volkow et al, 2001;McCann et al, 2008) and rodents (McFadden et al, 2012;Kousik et al, 2014) cause long-term striatal dopaminergic deficits resembling some aspects of Parkinson's disease (PD) (McCann et al, 1998;Lotharius and Brundin, 2002;Kish et al, 2008). In fact, individuals with a history of amphetamine (AMPH)/METH abuse have an increased risk for developing PD (Callaghan et al, 2010(Callaghan et al, , 2012Curtin et al, 2015).…”